Recent studies in many laboratories have demonstrated the presence of 2 ubiquitous, closely related enzymes, the calcium-activated proteases (CAP I and II). In brain, the CAP enzymes act on neurofilament proteins and lead to the degradation of these neuronal components. The neurofilament proteins, are also observed to be structurally altered in the brains of patients suffering from Alzheimer's disease and related dementias. The goal of this project is to immunochemically examine the possible involvement of CAP activity in the neuronal lesions of dementia, and see if altered protease activity is a biochemical factor in Alzheimer's disease. The phase I work will mainly involve the production of monoclonal antibodies to purified CAP I and II by highly efficient immunization, fusion and screening procedures. Appropriate antibodies will then be used to immunohistochemically localize the enzymes in brain tissue to see if the enzyme (or loss of enzyme) is coincident with the lesions ("plaques" and "tangles") seen in the Alzheimer's brain. At the end of Phase I, we would expect to have highly specific antibodies and be determining the enzymes precise location in mammalian brain. We believe this work will provide important new research tools, and may offer the opportunity for new diagnostic (in vivo imaging) and therapeutic (CAP modulation) approaches to Alzheimer's disease.